1. Field of the Invention
This invention relates generally to novel DNA sequences encoding cationic amino acid transporters. More particularly, the present invention relates to novel methods of using these DNA sequences and antibodies against the proteins expressed to treat pathophysiological diseases.
2. Description of the Related Art
The y.sup.+ transport system facilitates exclusively the transport of the cationic amino acids (AAs) arginine, lysine and ornithine in a sodium independent manner. An isolation of a cationic AA transporter cDNA clone (termed herein the mCAT-1 gene by Dr. J. Cunningham at Harvard Medical School has recently been reported. Other cDNA clones, isolated by more direct experiments, encode proteins that modify AA transport but are unlikely to directly transport AAs. These proteins are termed accessory or activator proteins.
The mCAT-2 gene was originally named the Tea gene. The gene is now designated murine cationic amino acid transporter (mCAT-2) because of its function as disclosed by the present invention.
Arginine is required for protein synthesis, plays a pivotal role in the biosynthesis of other AAs and is the direct precursor of urea in the urea cycle. Arginine is required for the synthesis of the primary energy phosphagen, creatine phosphate, by donating an amidine group to glycine in the first step of creatine synthesis. The liver is not a net provider of arginine due to the very high level of arginase. Arginine exchange between the kidney and the circulation requires transport mechanisms both to export arginine and import it from glomerular filtrate. Hence, every organ in the body, apart from liver and kidney, derives arginine from the plasma via transport mechanisms. In contrast, lysine is an essential AA, i.e., must be obtained from dietary sources. It is not synthesized by mammals; hence all cells must be capable of transporting lysine to carry out protein synthesis.
Arginine has potent secretagogue activities on several endocrine glands. Intravenous or oral administration of arginine to adult humans induces pituitary growth hormone, prolactin and insulin secretion. In addition, arginine has effects on the immune system independent of polyamine synthesis.
Arginine is the sole precursor for the synthesis of nitric oxide (NO). NO is the most potent vasodilator known and is essential for macrophages and T cells to carry out their normal functions. The cytotoxic activity of macrophages is dependent on NO, the production of NO in the vascular endothelium regulates blood pressure, and NO is a neurotransmitter. Like all free radicals, NO is extremely reactive and consequently highly unstable and is rapidly converted to nitrate and nitrite. NO production is regulated, in part, by IL2, TNF-alpha and INF-gamma.
The prior art remains deficient in the lack of effective mechanisms to regulate NO production. The present invention overcomes this longfelt need in the art.